Fibromyalgia is a disease in which chronic and systemic strong pain or, even partially, chronic pain within a broad area is a main symptom and the pain is sometimes noted not only in muscle tissues but also in the skin. The fibromyalgia is often accompanied not only with systemic chronic pain as such but also with sense of fatigue, malaise, depression, anxiety, muscle tightness in the morning, muscle stiffness and sleep disorders. It is also sometimes accompanied with headache, facial pain, dysgnosia (lapse of memory, lack of concentration), gastrointestinal complaint (visceral pain, disorder of digestive system and flatulence), pollakiuria, diarrhea, constipation, dysmenorrhea, etc.
Prevalence rate of fibromyalgia to the general population in the United States has been reported to be 3.4% for women and 0.5% for men. It occurs frequently in females of about 25 to 50 years age and about 80% of the patients are females. The situation in Japan is believed to be nearly the same as that in the United States. In fibromyalgia, subjective symptoms are variegated while its objective opinion are not too much except its characteristic systemic pressure pain. Even when not only image diagnosis such as MRI and CT but also pathological test of muscular pain sites and various immunological, virological and endocrinological tests are carried out, abnormal observation is rarely noted. For example, unlike rheumatic arthritis, no edema is observed and, in spite of the fact that the index in blood showing the degree of inflammation such as erythrocyte sedimentation rate and CRP is within a normal range, patients complain pain in broad areas of extremity and body trunk.
With regard to a diagnostic method therefor, the classification criteria proposed by the American College of Rheumatologyin 1990 have been used throughout the world at present. In the criteria, the case where pain is noted in all of the five areas of upper, lower, right and left halves of the body where the umbilical region is a cardinal point and also vertebral and sternal part and said pain continues at least for three months or the case where, when a mild load of 4 kg is applied to the stipulated 18 areas throughout the body, pain is noted in 11 or more areas is diagnosed as fibromyalgia.
At present, cause and mechanism of onset of fibromyalgia are presumed to be psychological elements such as stress, viral infection, heredity, abnormality in immunity and in neurotransmitters although they have not been clarified yet. Fibromyalgia is a disease which is quite different from many common pain diseases caused by injury of biological tissues or nociceptive stimulus which may cause injury and no related pathological observation is noted in the painful site.
In the treatment of fibromyalgia, most of anti-inflammatory and analgesic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) which have been frequently used for the treatment of common pain are ineffective. Although various drugs such as muscle relaxants, opioid analgesics and antianxiety agents have been tried, their efficacy greatly varies among individuals and no significant effect is noted. Accordingly, at present, for the treatment of fibromyalgia, prescription of antidepressants or a combination thereof with NSAIDs, administration of local anesthetic or steroidal agent to painful site, massage, therapeutic exercise, sleep therapy, etc. have been merely applied. However, in any of the therapeutic agents and methods, difference in the therapeutic effect among individuals is big partly because the cause for fibromyalgia has not been specified yet, whereby no therapeutic method has been established yet.
As mentioned above, cause and mechanism of onset of fibromyalgia have not been clarified yet at present and, therefore, there has been a demand for a method of studying, determining or evaluating the substances which are effective for this disease.
An object of the present invention is to provide a method for study, determination or evaluation of a substance which is effective for fibromyalgia or pain diseases.
The present inventors have firstly paid their attention to the similarities between fibromyalgia and SART stressed animals.
SART stressed animals are the animals which are loaded with SART (specific alternation of rhythm in temperature) stress, in other words, a repetitive cold stress and mice, rats, guinea pigs and the like are able to be prepared. Method of preparation is able to be carried out in accordance with a method of Kita, et al. (Folia Pharmacologica Japonica, 71:195, 1975). For example, in the case of rats, temperature for breeding environment is changed at 24° C. and −3° C. every one hour from 10 a.m. to 5 p.m., then it is kept at 4° C. from 5 p.m. to 10 a.m. of the next morning. Thus, the repetitive cold stress is loaded by breeding for 4 days or more where water and feed are freely taken by them whereupon the SART stressed rats are prepared. The temperature setting of as low as −3° C. in the case of rats is changed to 4° C. for mice and to 0° C. for guinea pigs whereupon SART stressed mice and SART stressed guinea pigs are able to be prepared respectively.
In the SART stressed animals prepared as such, there have been known such characteristics that their pain threshold values lower due to the repeated cold stress (pain sensitivity), anxiety and depression are promoted, release of CRH (corticotropin-releasing hormone), noradrenaline and IL-1β is promoted and release of serotonin (5-HT) is suppressed. Body weight decreases as well.
On the other hand, it has been also known that, in the patients suffering from fibromyalgia, there are characteristics that pain threshold value lowers, anxiety and depression are promoted, release of CRH (corticotropin-releasing hormone), noradrenaline, substance P, IL-1β, IL-2, IL-6 and IL-8 is promoted and release of serotonin (5-HT) is suppressed. It has been found that, with regard to those respects, fibromyalgia has a common point with SART stressed animals.
In the meanwhile, it has been known already that, in SART stressed animals, an extract from inflamed tissues inoculated with vaccinia virus has an antistress action such as a suppressive action for lowering of pain threshold (pain sensitivity) (analgesic action), a suppressive action for promotion of release of CRH (corticotropin-releasing hormone), noradrenaline and IL-1β and for suppression of release of serotonin (5-HT) and a suppressive action for body weight decrease (Kiso to Rinsho, volume 15, No. 5, page 2459, 1981; Pharmacometrics (Oyo Butsuri), volume 32, No. 3, page 599, 1986; etc.). The titer determination of a pharmaceutical preparation that an extract from inflamed rabbit skin inoculated with vaccinia virus is an effective ingredient (trade name: Neurotropin) is conducted by means of analgesic effect test using the SART stressed animals, which is defined as a quantitative test therefor.
The preparation of an extract from inflamed rabbit skin inoculated with vaccinia virus is a very unique preparation which has been allowed to be used for a broad range of indications such as itch accompanied by skin diseases (such as eczema, dermatitis and urticaria), allergic rhinitis and secuelae of SMON (coldness, paresthesia/dysesthesia, pain, etc.) in addition to painful diseases such as low back pain, neck-shoulder-arm syndrome, symptomatic neuralgia, periarthritis scapulohumeralis, degenerative arthritis deformans and post-herpetic neuralgia. Injection preparations for hypodermic, intramuscular and intravenous uses and tablet preparations have been approved to manufacture as ethical drugs and put into the market. In recent years, clinical tests therefor have been carried out in the United States for RSD (reflex sympathetic dystrophy, CRPS-type 1) which is an intractable neuropathic pain.
It has been also found in recent years that the extract from inflamed tissues inoculated with vaccinia virus is effective for fibromyalgia (Arthritis Res. Ther., 5 (Suppl. 3): S53, 170, 2003; etc.). The fact that the extract from inflamed tissues inoculated with vaccinia virus is effective for fibromyalgia is mentioned in the following Patent Document.
Patent Document 1: International Publication WO 2004/039,383